AbstractObjectivesEsophagogastroduodenoscopy (EGD) is vital for diagnosing and treating upper gastrointestinal symptoms, but patient discomfort and anxiety can affect procedural outcomes. This study aimed to compare the effectiveness of topical analgesics with and without Entonox during EGD in terms of procedural success, patient tolerance, and satisfaction.MethodsA prospective, randomized, double‐blinded, controlled trial. Patients were assigned to receive either 10% xylocaine spray in the control group (Group C) or 10% xylocaine spray combined with Entonox (Group E). Procedural success and patient comfort were evaluated using the Bath Gastroscopy Toleration Score and patient comfort scores, with scores of 0 or 1 indicating success. Satisfaction was measured using the numeric rating scale, where scores of 7 or higher indicated high satisfaction.ResultsA total of 211 patients underwent EGD successfully (Group C = 106, Group E = 105). Patients in Group E demonstrated a significantly higher proportion of success rate (76.2% vs. 35.9%, p < 0.001), better toleration score (82.9% vs. 75.5%, p = 0.004), and better patient comfort score (86.7% vs. 39.6%, p < 0.001) compared to Group C. Endoscopists and patients in Group E expressed higher satisfaction levels (9 vs. 8, p < 0.01 and 9 vs. 8, p < 0.01). The side effects of Entonox were minimal. Notably, Group E had a lower proportion of high blood pressure and tachycardia during the procedure (p < 0.001).ConclusionsCombining Entonox with topical analgesics significantly improves tolerance, satisfaction, and procedural success during EGD, offering a safe and effective option for managing patient discomfort and anxiety.